Musculoskeletal extremity injuries comprise ~50% of all combat wounds for OIF/OEF/OND Veterans. Blast injuries via improvised explosive devices account for over 75% of combat casualties, with survivors experiencing severe orthopedic injuries. These types of orthopedic injuries often result in delayed or non-union, wherein normal bone healing is impaired. Current interventions for non-union fractures, particularly atrophic non-union fractures are rarely successful. OIF/OEF/OND Veterans are also at a high risk for depressive and depressive-associated disorders including post-traumatic stress disorder (PTSD), resulting in >60% of this population being prescribed antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs). While the effects of SSRIs on fracture healing are unknown, it has been shown that Sertraline (Zoloft) and Paroxetine (Paxil), first-line SSRIs for pharmacological treatment of these disorders, negatively affect bone health. Given the prevalence of complex orthopedic injuries, the long-term complications from these injuries, and the commonness of SSRI use in the OIF/OEF/OND Veteran population, there is a need for new therapies (e.g., cell-based therapies) that may overcome current clinical limitations for complicated fractures. Our studies using a unique clonal cell transplantation model in conjunction with murine fracture models has identified the hematopoietic stem cell (HSC) as a novel progenitor for osteoblasts, osteocytes, and chondrocytes during fracture repair. Recent studies show HSC-derived osteoprogenitors directly give rise to bone in vivo. These findings are paradigm shifting in that most studies focus on the use of mesenchymal stem cells (MSCs) for musculoskeletal injury repair and suggest a benefit of HSC-based therapies for complicated fracture. Building on our previous MERIT studies, which demonstrated a role for bone morphogenetic protein-2 (BMP-2), BMP-9, and insulin-like growth factor (IGF-2) in promoting osteogenesis from the HSC, we have now shown a combination of IGF-2+BMP-9 results in enhanced osteoinduction from HSC-osteogenic precursors. We have also identified HSC-derived circulating osteogenic progenitors (COPs) that increase in blood during normal fracture repair and are mobilized with AMD3100 delivery, suggesting a potential therapeutic modality. Our preliminary data also demonstrate that SSRI administration in vivo leads to impaired bone healing, results in altered osteogenic profiles during healing, and inhibits osteoinduction from HSC-progenitors in vitro. We hypothesize that HSC-derived osteo-chondrogenic progenitor cells may be targeted to enhance repair of complicated fractures. Our goals are to examine the ability of HSC-derived osteo-chondrogenic progenitors (compared to MSCs) to serve as a therapeutic modality during complicated non-union fractures and fractures during SSRI administration, uncover the mechanisms by which these cells may have a beneficial effect, and elucidate the effects of SSRIs on this unique population of progenitor cells. Specific Aims are to determine 1) if modulation of HSC-derived osteo-chondrogenic precursors in vivo promotes healing in a model of atrophic non-union and 2) if SSRIs impair fracture healing via inhibition of HSC-derived osteogenic precursors. These studies are significant in that they challenge existing dogma by suggesting a novel HSC origin for bone cells and innovative in that they will determine the potential of exploiting HSCs to enhance healing in cases of complicated fracture. Findings from this study are easily translated to clinic (HSC mobilization is FDA approved for other applications) and have the potential to directly impact Veteran Health Care. Understanding how SSRIs affect bone healing and specific stem cell compartments may have tremendous clinical impact given the large number of injured Veterans prescribed SSRIs. This work will have far-reaching benefit for military personnel and Veterans at high risk for complicated fracture, specifically those of OIF/OEF/OND being treated for clinical depression and/or PTSD using an SSRI, and thus, is highly relevant to the VA Mission.